CN101366700B - Hydrophilic medicament dual-microsphere formulation and preparation method thereof - Google Patents
Hydrophilic medicament dual-microsphere formulation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a dual microsphere preparation of a hydrophilic drug, which consists of the hydrophilic drug, chitosan, sodium tripolyphosphate and a polylactic acid-glycolic acid copolymer. The invention also discloses a method for preparing the dual microsphere preparation: firstly, chitosan nanoparticles of the hydrophilic drug are prepared; secondly, the nanoparticles are dispersed in an acetonitrile or dichloromethane solution of PLGA and are evenly mixed to be used as suspension aqueous phase; finally, span80 is dissolved in edible oil to be used as oil phase; the oil phase is slowly dripped to the suspension aqueous phase while being stirred; acetonitrile or dichloromethane is removed; and the mixture is subjected to centrifugal collection and vacuum drying to prepare the dual microsphere preparation. The dual microsphere preparation of the hydrophilic drug has small burst effect, keeps the high encapsulation efficiency of the chitosan nanoparticles to the hydrophilic drug, is slowly released in vitro and is novel promising slow-release dosage of the hydrophilic drug.
Description
Technical field
The present invention relates to the biodegradable microball preparation field in the pharmaceutics, be specifically related to a kind of dual-microsphere formulation that adopts chitosan-modified hydrophobicity degradable poly lactic acid-ethanol copolymer parcel hydrophilic medicament and preparation method thereof.
Background technology
Polylactic-co-glycolic acid (PLGA) is the high-molecular copolymer that is polymerized under the effect of catalyst by lactic acid (LA) and two kinds of monomers of glycolic (GA).PLGA has favorable biological degradability and biocompatibility, can be degraded into lactic acid, water and carbon dioxide in vivo, participates in intravital metabolism, can not cause any toxic reaction in vivo.But extensive use and biomedical tissue engineering absorb suture material, the fixing tissue renovation material etc. that reaches of orthopaedics as controlled drug delivery system, organism.This material can be used for the device of slow releasing pharmaceutical carrier and the implantation of other human bodies by drugs approved by FDA.Medicine through the PLGA embedding, is made sustained-release micro-spheres, can improve the bioavailability of medicine, reduce administration number of times and dose, alleviate patient's misery, reduce medicine to greatest extent the whole body toxic and side effects of liver, kidney particularly.PLGA is used for preparing the fat-soluble medicine microball preparation more at present, as dexamethasone, paclitaxel, amycin etc., report for hydrophilic medicament is less, and focus mostly in the hydrophilic macromolecular drug, as interferon-' alpha ', albumin, insulin, nucleic acid etc., the rarer successful example of mentioning preparation hydrophilic medicament microsphere, it is main because hydrophilic medicament and macromolecular material PLGA affinity are poor, be easy to be diffused into aqueous phase and cause drug loading or envelop rate not high, the actual drug loading of PLGA microsphere of this class hydrophilic medicament only has 9.8 μ g/mg in the report that has.
The existing literature report microspheres that adopt multi-emulsion method to prepare hydrophilic medicament more, promptly at first the dichloromethane solution of pharmaceutical aqueous solution and PLGA is mixed and made into colostrum, colostrum is poured in the aqueous solution that contains emulsifying agent made emulsion, solvent flashing then, washing obtains microsphere after the lyophilizing.The PLGA microsphere of albumen, polypeptide drug is fit to the multi-emulsion method preparation, and the microsphere drug loading that obtains when still adopting multi-emulsion method to prepare hydrophilic medicament (as water soluble antibiotics) is often undesirable, and has tangible burst effect.The reason that drug loading is low may be that hydrophilic medicament and macromolecular material PLGA affinity are poor, is easy to be diffused into aqueous phase in preparation process and causes drug loading or envelop rate not high; Prominent releasing may be because little and porous microsphere has bigger surface area, and drug release is accelerated, also may by medicine in process of vacuum drying by to flowing to diffusion into the surface, cause microsphere surface to gather due to the high amount of drug.Prominent releasing might increase side effects of pharmaceutical drugs, also may cause drug waste and makes microsphere can't keep long-term release.
Publication number is that the Chinese patent of CN1268325C discloses a kind of triple complex microsphere preparations and preparation method thereof, earlier the hydrophilic macromolecular drug is wrapped up dual microcapsule, again this microcapsule is prepared into alginic acid-chitosan-PLGA complex microsphere into alginic acid-chitosan.For the hydrophilic small molecules medicine, though use this legal system to be equipped with the burst effect that dual-microsphere can be controlled microball preparation, the low problem of envelop rate has but appearred, cause wastage of material and can't reach the purpose of long-term slow release.
Publication number is that the Chinese patent application of CN1813684A discloses a kind of preparation method for preparing 5-fluorouracil/chitosan nano drug-carrying microsphere, is used to prolong the drug effect at the molten 5-fluorouracil of water part omitted, reduces its toxic and side effects.The microball preparation that adopts a step parcel to prepare not only have tangible burst effect, and the lasting release time of medicine is shorter.
Summary of the invention
The invention provides dual-microsphere formulation of a kind of hydrophilic medicament and preparation method thereof, earlier hydrophilic medicament is dissolved in chitosan solution and prepares chitosan nano, again chitosan nano is prepared into chitosan-PLGA dual-microsphere, not only simplified preparation technology widely, kept the prominent advantage of releasing of dual-microsphere control, and chitosan nano has higher entrapment to hydrophilic medicament (especially hydrophilic small molecules medicine), thereby increased substantially the drug loading of dual-microsphere, made long-term slowly release of hydrophilic medicament become possibility.
A kind of hydrophilic medicament dual-microsphere formulation is made up of hydrophilic medicament, chitosan, sodium tripolyphosphate and polylactic-co-glycolic acid.
A kind of preparation method of hydrophilic medicament dual-microsphere formulation may further comprise the steps:
(1) preparation of chitosan nano:
It is that 0.25～5mg/ml, pH value are 4～6 chitosan aqueous solution that hydrophilic medicament is dissolved in concentration, slowly add the tripolyphosphate sodium water solution while stirring, mix homogeneously, at 3～5 ℃ of centrifugal back of rotating speed 12000～20000rpm collecting precipitation things, distillation washing postlyophilization makes chitosan nano, wherein the concentration of hydrophilic medicament in chitosan aqueous solution is 0.5～50mg/ml, and chitosan and sodium tripolyphosphate mass ratio are 2:1～10:1.
(2) preparation of chitosan-PLGA dual-microsphere:
The chitosan nano of step (1) preparation is dispersed in the acetonitrile or dichloromethane solution that PLGA concentration is 0.03～0.25g/ml, and mix homogeneously is as the suspendible water; Sorbester p17 is dissolved in edible oil as oil phase by the concentration of 0.02～0.15g/ml in edible oil; The volume ratio of acetonitrile or dichloromethane and edible oil is 1:3～1:25; While stirring oil phase is slowly splashed into above-mentioned suspendible water, reduction vaporization is removed acetonitrile or dichloromethane, centrifugal collection dual-microsphere, petroleum ether final vacuum drying promptly makes hydrophilic medicament dual-microsphere formulation, and wherein the mass ratio of chitosan nano and PLGA is 1:2～1:10.
Described hydrophilic medicament is that beta-lactam antibiotic, macrolide antibiotics, aminoglycoside antibiotics, Tetracyclines, chloromycetin, polypeptide class, protein medicaments or other need the hydrophilic medicament of slow release.
Described beta-lactam antibiotic can be selected penicillin, amoxicillin, ampicillin, mezlocillin, cefalexin, cefalotin, cefazolin sodium, cefaclor, Cefuroxime Sodium, cefoxitin, ceftriaxone, cefotaxime, cefepime, cefpirome, cefradine, meropenem, faropenem, aztreonam etc. for use.
Described macrolide antibiotics can be selected erythromycin, midecamycin, spiramycin, acetylspiramycin, josamycin, kitasamycin, azithromycin, clarithromycin, Roxithromycin etc. for use.
Described aminoglycoside antibiotics can be selected streptomycin, neomycin, paromomycin, kanamycin, dibekacin, amikacin, ribostamycin, gentamycin, sisomicin, netilmicin, micronomicin etc. for use.
Described tetracycline antibiotics can be selected tetracycline, oxytetracycline, chlortetracycline, doxycycline, minocycline, beautiful his mycin etc. for use.
Described chloromycetin series antibiotics can be selected chloromycetin, thiamphenicol, chloramphenicol palmitate etc. for use.
Described polypeptide drug can select for use thyroliberin, vassopressin, oxytocin, gastrin, thyrotrophin-releasing hormone, new deltorphin delta, paddy to take off sweet peptide, calcitonin, Thymosin alpha
1Deng.
Described protein medicaments can be selected interferon, insulin, erythropoietin, interleukin, human growth hormone etc. for use.
Described polylactic-co-glycolic acid (PLGA), its lactic acid (LA) is 90～50:10～50 with the mass ratio of glycolic (GA), molecular weight is 5000～300,000.PLGA can form the skeleton of microsphere, slow hydrolysis, corrosion take place until disintegrate in the diffusion along with hydrone in aqueous medium, medicine is released in the medium thereupon and goes, performance with certain control drug release, and its catabolite is nontoxic to human body, is a kind of good controlled release preparation framework material.Can further prolong hydrophilic medicament with PLGA parcel chitosan nano and continue release time, reach the purpose of dual-sustained-release.
Described edible oil is a daily life edible oil commonly used.
Chitosan is (pH4～6 under acid condition, available acetic acid is regulated pH value) the water-soluble chitosan aqueous solution that is mixed with, this solution and hydrophilic medicament affinity are strong, the prepared chitosan nanoparticle has higher entrapment to water soluble drug, can remedy the simple PLGA microsphere defective low to the water soluble drug envelop rate, on the other hand, amino on the chitosan molecule has cushioning effect to a large amount of hydrions that the PLGA biodegradation produces, can reduce degraded or the loss of activity of some drugs under acid condition, reduce the incomplete release rate of medicine in microsphere to a certain extent.
Sodium tripolyphosphate can make chitosan molecule that crosslinked balling-up then take place with chitosan generation electrostatic interaction, and in vivo natural decomposition to human body nonhazardous effect.
The present invention compared with prior art has following advantage:
(1) the present invention adopts the chitosan-modified hydrophobicity PLGA of hydrophilic biodegradable polymer microsphere, the initial release amount of PLGA microsphere is effectively controlled, and the external accumulative total burst size of modified dual-microsphere 24 hours is 1/2 of not modified PLGA microsphere;
(2) the dual-microsphere particle size distribution that makes of the present invention is even, and envelop rate height, drug release continue slowly can keep 10～120 days release;
(3) preparation method provided by the present invention is suitable for multiple hydrophilic medicament, and particularly easily molten medicine in water has broad application prospects;
(4) in preparation chitosan nano process, selected freeze-drying for use, can effectively protect heat-sensitive substance, make its unlikely degeneration or lose vigor, dry back volume is almost constant, can not shrink phenomenon, and it is loose porous spongy that material is, dissolving rapidly after adding water, dry back product is long preservation at room temperature, and the transportation that is easy to carry easily realizes commercialization production;
(5) further wrap up chitosan nano with PLGA after finishing the preparation of chitosan nano, reached the purpose of dual-sustained-release.
Description of drawings
Fig. 1 is the dual-microsphere particle size distribution figure of embodiment 3 preparations;
Fig. 2 is the dual-microsphere sem photograph of embodiment 3 preparations;
Fig. 3 is the dual-microsphere formulation cumulative in vitro release profiles of embodiment 4 preparations.
The specific embodiment
Comparative Examples: multi-emulsion method prepares the hydrophilic medicament microball preparation
Take by weighing PLGA (mass ratio of LA and GA is 75:25) 100mg and be dissolved in the 2ml dichloromethane, cefazolin sodium 25mg is dissolved in the 0.2ml distilled water, biphase in 200w probe type ultrasonic instrument after ultrasonic 90 seconds, pour the outer aqueous phase that 200ml contains 0.02g/ml polyvinyl alcohol (PVA), 0.005g/ml NaCl rapidly into, 10000rpm breast at a high speed spares 1 minute, rotary evaporation 40 minutes, centrifugal 10 minutes of 3000rpm, twice postlyophilization of distillation washing makes the cefazolin sodium microball preparation.
Embodiment 1
Precision takes by weighing the 30mg gentamycin, be dissolved in the chitosan aqueous solution that 30ml concentration is 1mg/mL, pH=6, the room temperature lower magnetic force stirs, with 12ml concentration is that the tripolyphosphate sodium water solution of 0.5mg/mL slowly adds chitosan solution, mixed 30 minutes, at 4 ℃ of rotating speed 12000rpm collecting precipitation thing after centrifugal 20 minutes, with distillation washing 3 times, lyophilization makes chitosan nano.
Above-mentioned dried 50mg chitosan nano is dispersed in the 2.5ml acetonitrile solution that contains 300mgPLGA (mass ratio of LA and GA is 90:10), and ultrasonic 90 seconds mix homogeneously of 400w probe type ultrasonic instrument are as the suspendible water; 1.5g sorbester p17 is dissolved in the 20ml edible oil as oil phase; Under 3500rpm stirs oil phase is slowly splashed into above-mentioned suspendible water, decompression rotary evaporation 2 hours is removed acetonitrile, centrifugal collection dual-microsphere, and petroleum ether is removed edible oil and sorbester p17, and vacuum drying promptly makes the gentamycin dual-microsphere formulation.
Embodiment 2
Precision takes by weighing the 30mg streptomycin, and all the other are operated with method by example 1 operating procedure.
Embodiment 3
Precision takes by weighing the 250mg tetracycline, be dissolved in the chitosan aqueous solution that 25ml concentration is 3mg/mL, pH=4, the room temperature lower magnetic force stirs, with 20ml concentration is that 1.5mg/mL tripolyphosphate sodium water solution slowly adds chitosan solution, mixed 40 minutes, at 4 ℃ of rotating speed 16000rpm collecting precipitation thing after centrifugal 20 minutes, with distillation washing 3 times, lyophilization makes chitosan nano.
Above-mentioned dried 50mg chitosan nano is dispersed in the 3ml acetonitrile solution that contains 200mgPLGA (mass ratio of LA and GA is 85:15), and ultrasonic 90 seconds mix homogeneously of 400w probe type ultrasonic instrument are as the suspendible water; 2.0g being dissolved in the 20ml edible oil, sorbester p17 under 3500rpm stirs, oil phase is slowly splashed into above-mentioned suspendible water as oil phase, decompression rotary evaporation 1.5 hours, remove acetonitrile, centrifugal collection dual-microsphere, petroleum ether is removed edible oil and sorbester p17, vacuum drying promptly makes the tetracycline dual-microsphere formulation, and the dual-microsphere particle size distribution figure of said preparation sees Fig. 1, and its mean diameter is 35.5 μ m.
Embodiment 4
Precision takes by weighing the 250mg oxytetracycline, and all the other are operated with method by example 3 operating procedures.
Embodiment 5
Precision takes by weighing the 80mg interferon, be dissolved in the chitosan aqueous solution that 50ml concentration is 0.5mg/mL, pH=5, the room temperature lower magnetic force stirs, with 18ml concentration is that 0.2mg/mL tripolyphosphate sodium water solution slowly adds chitosan solution, mixed 20 minutes, at 4 ℃ of rotating speed 14000rpm collecting precipitation thing after centrifugal 25 minutes, with distillation washing 3 times, lyophilization makes chitosan nano.
Above-mentioned dried 50mg chitosan nano is dispersed in the 4ml acetonitrile solution that contains 250mgPLGA (mass ratio of LA and GA is 60:40), and ultrasonic 90 seconds mix homogeneously of 200w probe type ultrasonic instrument are as the suspendible water; 2.5g sorbester p17 is dissolved in the 30ml edible oil as oil phase; Under 3500rpm stirs oil phase is slowly splashed into above-mentioned suspendible water, decompression rotary evaporation 1 hour is removed acetonitrile, centrifugal collection dual-microsphere, and petroleum ether is removed edible oil and sorbester p17, and vacuum drying promptly makes the interferon dual-microsphere formulation.
Embodiment 6
Precision takes by weighing the 80mg insulin, and all the other are operated with method by example 5 operating procedures.
Embodiment 7
Precision takes by weighing the 300mg cefradine, be dissolved in the chitosan aqueous solution that 16ml concentration is 5mg/mL, pH=4, the room temperature lower magnetic force stirs, with 12ml concentration is that 3.3mg/mL tripolyphosphate sodium water solution slowly adds chitosan solution, mixed 40 minutes, at 4 ℃ of rotating speed 15000rpm collecting precipitation thing after centrifugal 20 minutes, with distillation washing 3 times, lyophilization makes chitosan nano.
Above-mentioned dried 50mg chitosan nano is dispersed in the 2ml acetonitrile solution that contains 350mgPLGA (mass ratio of LA and GA is 65:35), and ultrasonic 90 seconds mix homogeneously of 400w probe type ultrasonic instrument are as the suspendible water; 1.5g sorbester p17 is dissolved in the 30ml edible oil as oil phase; Under 5000rpm stirs oil phase is slowly splashed into above-mentioned suspendible water, decompression rotary evaporation 30 minutes is removed acetonitrile, centrifugal collection dual-microsphere, and petroleum ether is removed edible oil and sorbester p17, and vacuum drying promptly makes the cefradine dual-microsphere formulation.
Embodiment 8
Precision takes by weighing the 300mg penicillin, and all the other are operated with method by example 7 operating procedures.
Embodiment 9
Precision takes by weighing 420mg chloromycetin, being dissolved in 12ml concentration is 2mg/mL, pH=4 chitosan aqueous solution, the room temperature lower magnetic force stirs, with 15ml concentration is that 0.4mg/mL tripolyphosphate sodium water solution slowly adds chitosan solution, mixed 30 minutes, at 4 ℃ of rotating speed 12000rpm collecting precipitation thing after centrifugal 20 minutes, with distillation washing 3 times, lyophilization makes chitosan nano.
Above-mentioned dried 50mg chitosan nano is dispersed in the 2ml dichloromethane solution that contains 300mgPLGA (mass ratio of LA and GA is 50:50), and ultrasonic 90 seconds mix homogeneously of 400w probe type ultrasonic instrument are as the suspendible water; 1.8g sorbester p17 is dissolved in the 25ml edible oil as oil phase; Under 3500rpm stirs oil phase is slowly splashed into above-mentioned suspendible water, decompression rotary evaporation 1 hour is removed dichloromethane, centrifugal collection dual-microsphere, and petroleum ether is removed edible oil and sorbester p17, and vacuum drying promptly makes the amoxicillin dual-microsphere formulation.
Embodiment 10
Precision takes by weighing the 420mg thiamphenicol, and all the other are operated with method by example 9 operating procedures.
Embodiment 11
Precision takes by weighing 60mg erythromycin, being dissolved in 30ml concentration is 0.3mg/mL, pH=5.5 chitosan aqueous solution, the room temperature lower magnetic force stirs, with 10ml concentration is that 0.2mg/mL tripolyphosphate sodium water solution slowly adds chitosan solution, mixed 30 minutes, at 4 ℃ of rotating speed 20000rpm collecting precipitation thing after centrifugal 20 minutes, with distillation washing 3 times, lyophilization makes chitosan nano.
Above-mentioned dried 50mg chitosan nano is dispersed in the 2ml acetonitrile solution that contains 300mgPLGA (mass ratio of LA and GA is 80:20), and ultrasonic 90 seconds mix homogeneously of 400w probe type ultrasonic instrument are as the suspendible water; 1.0g sorbester p17 is dissolved in the 20ml edible oil as oil phase; Under 3500rpm stirs oil phase is slowly splashed into above-mentioned suspendible water, decompression rotary evaporation 2 hours is removed acetonitrile, centrifugal collection dual-microsphere, and petroleum ether is removed edible oil and sorbester p17, and vacuum drying promptly makes the erythromycin dual-microsphere formulation.
Embodiment 12
Precision takes by weighing the 420mg azithromycin, and all the other are operated with method by example 11 operating procedures.
Embodiment 13
Precision takes by weighing the 560mg calcitonin, being dissolved in 30ml concentration is 1.0mg/mL, pH=5 chitosan aqueous solution, the room temperature lower magnetic force stirs, with 10ml concentration is that 0.5mg/mL tripolyphosphate sodium water solution slowly adds chitosan solution, mixed 30 minutes, at 4 ℃ of rotating speed 20000rpm collecting precipitation thing after centrifugal 20 minutes, with distillation washing 3 times, lyophilization makes chitosan nano.
Above-mentioned dried 60mg chitosan nano is dispersed in the 3ml acetonitrile solution that contains 250mgPLGA (mass ratio of LA and GA is 75:25), and ultrasonic 90 seconds mix homogeneously of 400w probe type ultrasonic instrument are as the suspendible water; 2.0g sorbester p17 is dissolved in the 25ml edible oil as oil phase; Under 4000rpm stirs oil phase is slowly splashed into above-mentioned suspendible water, decompression rotary evaporation 2.5 hours is removed acetonitrile, centrifugal collection dual-microsphere, and petroleum ether is removed edible oil and sorbester p17, and vacuum drying promptly makes the erythromycin dual-microsphere formulation.
Embodiment 14
Precision takes by weighing the 560mg thyrotrophin-releasing hormone, and all the other are operated with method by example 13 operating procedures.
The present invention organizes in contrast with Comparative Examples, its drug loading is 7.6 μ g/mg, embodiment 1～14 has changed conditions such as the proportioning, solvent evaporates time of drug level, chitosan concentration, chitosan solution acidity, PLGA concentration, chitosan nano and PLGA, and has obtained the chitosan-PLGA dual-microsphere formulation of different envelop rates, different burst effects.24 hours cumulative in vitro release rates of dual-microsphere formulation data of Comparative Examples and embodiment 1～14 preparation see Table 1; The dual-microsphere envelop rate data of Comparative Examples and embodiment 1～14 preparation see Table 2; The chitosan nano particle size data of embodiment 1 preparation sees Table 3; The dual-microsphere particle size distribution data of embodiment 3 preparations sees Table 4.
Table 1
| Project | 24h cumulative release percentage rate (%) | Project | 24h cumulative release percentage rate (%) |
| Comparative Examples | 48.0 | Embodiment 8 | 25.5 |
| Embodiment 1 | 23.7 | Embodiment 9 | 24..0 |
| Embodiment 2 | 25.5 | Embodiment 10 | 07.3 |
| Embodiment 3 | 24.0 | Embodiment 11 | 26.6 |
| Embodiment 4 | 27.3 | Embodiment 12 | 23.8 |
| Embodiment 5 | 26.6 | Embodiment 13 | 22.5 |
| Embodiment 6 | 23.8 | Embodiment 14 | 22.5 |
| Embodiment 7 | 23.7 |
Table 2
| Project | Envelop rate (%) | Project | Envelop rate (%) |
| Comparative Examples | 3.8 | Embodiment 8 | 35.0 |
| Embodiment 1 | 40.2 | Embodiment 9 | 37.2 |
| Embodiment 2 | 41.5 | Embodiment 10 | 36.4 |
| Embodiment 3 | 36.2 | Embodiment 11 | 38.2 |
| Embodiment 4 | 38.4 | Embodiment 12 | 36.6 |
| Embodiment 5 | 39.1 | Embodiment 13 | 39.5 |
| Embodiment 6 | 35.7 | Embodiment 14 | 40.1 |
| Embodiment 7 | 43.8 |
Table 3
| Project | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 | Embodiment 10 | Embodiment 11 | Embodiment 12 | Embodiment 13 | Embodiment 14 |
| Particle diameter (nm) | 203 | 320 | 260 | 360 | 280 | 220 | 250 | 270 | 320 | 245 | 267 | 230 | 258 | 266 |
Table 4
| Particle diameter (μ m) | 18.75 | 22.76 | 27.63 | 33.54 | 40.72 | 49.43 | 60.00 | 72.84 | 88.42 |
| Volume (%) | 0.00 | 0.74 | 13.26 | 30.35 | 32.33 | 20.07 | 2.98 | 0.27 | 0.00 |
| Cumulative volume percentage rate (%) | 0.00 | 0.74 | 14.00 | 44.35 | 76.68 | 96.75 | 99.73 | 100.00 | 100.00 |
Claims (2)
1. the preparation method of a hydrophilic medicament dual-microsphere formulation may further comprise the steps:
(1) preparation of chitosan nano
It is that 0.25～5mg/ml, pH value are 4～6 chitosan aqueous solution that hydrophilic medicament is dissolved in concentration, slowly add the tripolyphosphate sodium water solution while stirring, mix homogeneously, at 3～5 ℃ of centrifugal back of rotating speed 12000～20000rpm collecting precipitation things, distillation washing postlyophilization makes chitosan nano, wherein the concentration of hydrophilic medicament in chitosan aqueous solution is 0.5～50mg/ml, and chitosan and sodium tripolyphosphate mass ratio are 2: 1～10: 1;
(2) preparation of dual-microsphere
The chitosan nano of step (1) preparation is dispersed in the acetonitrile or dichloromethane solution that polylactic-co-glycolic acid concentration is 0.03～0.25g/ml, and mix homogeneously is as the suspendible water; Sorbester p17 is dissolved in edible oil as oil phase by the concentration of 0.02～0.15g/ml in edible oil; The volume ratio of acetonitrile or dichloromethane and edible oil is 1: 3～1: 25; While stirring oil phase is slowly splashed into above-mentioned suspendible water, reduction vaporization is removed acetonitrile or dichloromethane, centrifugal collection dual-microsphere promptly makes hydrophilic medicament dual-microsphere formulation with petroleum ether final vacuum drying, and wherein the mass ratio of chitosan nano and PLGA is 1: 2～1: 10;
Described hydrophilic medicament is penicillin, cefradine, erythromycin, azithromycin, streptomycin, gentamycin, tetracycline, oxytetracycline, chloromycetin, thiamphenicol, thyrotrophin-releasing hormone, calcitonin, interferon or insulin;
Described polylactic-co-glycolic acid, the mass ratio of its lactic acid and glycolic are 90～50: 10～50, and molecular weight is 5000～300,000.
2. preparation method as claimed in claim 1 is characterized in that: the particle diameter that makes hydrophilic medicament dual-microsphere formulation in the step (2) after the drying is 0.1～200 μ m.
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| CN104628164B (en) * | 2013-11-11 | 2016-05-25 | 中国石油化工股份有限公司 | A kind of composition and application thereof for disinfecting corrosion inhibitor |
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